Mitochondrial Transfer: The making of three-parent babies

by Catherine Weiner figures by Rebecca Clements

The question, “where do babies come from?” used to have a simple answer. A man and woman have sex, the male sperm fertilizes the female egg, and 9 months later a baby is born. But in today’s world, medical advances have complicated this answer. For example, a new technique called mitochondrial transfer has recently emerged to prevent the transmission of a certain class of genetic disorders. This technique is highly controversial, as it combines DNA from three individual to generate a so-called “three-parent baby”.

What are Mitochondrial Disorders?

Just as our bodies have organs that perform particular functions, each cell within the body has small structures, aptly termed organelles, which have specific, life-sustaining jobs. For example, one of the primary organelles in each cell is the nucleus, which contains our DNA, or genetic information. Another type of organelle is mitochondria, which function to provide our cells, and thus our bodies, with energy. Interestingly, mitochondria also contain a very small amount of DNA, making them the only organelle other than the nucleus to house genetic information (Figure 1).

Figure 1: DNA in human cells. Our DNA is primarily in the nucleus, but a small amount is also in the mitochondria

Similar to nuclear DNA, mitochondrial DNA serves an important purpose, namely providing the genetic blueprint for molecular machines called proteins that carry out cellular functions. However, this capacity of mitochondria to carry DNA also makes them a genetic liability of sorts. Specifically, just like nuclear DNA, mitochondrial DNA is susceptible to mutations in the DNA code that can cause disease. If these DNA mutations lead to the production of damaged mitochondrial proteins, they can cause a class of diseases termed mitochondrial disorders.

Mitochondrial disorders are fairly common, affecting at least 1 in 5,000 births in the United States, and they exhibit a very unique inheritance pattern. Unlike nuclear DNA, which is passed in equal parts to a child from both parents, mitochondria are inherited solely from mothers. As such, if a mother has damaged mitochondrial DNA, she will pass this on to all of her children causing disease of a varied severity depending on the proportion of healthy and damaged mitochondria the child randomly inherits.

What is Mitochondrial Transfer?

Mitochondrial disorders can be devastating for couples trying to conceive. For example, one couple experienced several miscarriages and lost two children under the age of seven to Leigh’s Syndrome, a mitochondrial disorder that causes severe neurodegeneration. While the mother was a carrier for the disease, she did not have neurological symptoms herself because only a fraction of the mitochondria in her cells carried damaged DNA. Determined to have a child, the couple turned to Dr. John Zhang, an infertility expert at the New Hope Fertility Center in New York City. For the first time in humans, Dr. Zhang and his team attempted to use technology that has been around since 1983– mitochondrial transfer.

Mitochondrial transfer works by replacing the damaged mitochondria in the mother’s egg with healthy mitochondria from another woman’s donor egg (Figure 2). The developing embryo now has nuclear DNA from the mother and father, as well as mitochondrial DNA from the donor egg. Dr. Zhang describes his work in a peer-reviewed article. In the case of his patient, this procedure resulted in the birth of a son without Leigh’s syndrome – seemingly curing an incurable disease.

This first child was referred to in the press as a “three-parent baby” when he was born in Mexico in 2016. This term is slightly misleading, as the child does not have an equal proportion of DNA from each parent. Rather, the majority of the child’s DNA is from his parents, with only a small fraction coming from the mitochondria of the donor egg or third parent.

Figure 2: Diagram of Mitochondrial Transfer. Doctors first remove the genetic material from the donor egg (purple), leaving an empty egg full of healthy mitochondria and other nutrients. Next doctors remove the genetic material from the mother’s egg (teal) and transfer it into the now empty donor egg. After the transfer, the newly engineered egg (purple + teal) is fertilized with the father’s sperm (dark teal) and then implanted into the mother’s womb.

Biological Concerns

Mitochondrial transfer and other assisted reproductive technologies have opened the door to a series of biological, ethical, and legal concerns in a world where designer babies could be just around the corner.

The use of mitochondrial transfer is controversial as there are still several safety concerns. For example, there are concerns that some mutant mitochondria may accidentally get carried over from the mother. If this carry-over occurs, many question if the child will develop a mitochondrial disorder later in life or pass on mitochondrial disorders to their offspring. Additionally, there are concerns about the side effects of having DNA from three parents in one person. Research in cell culture or in primates suggests that these issues do not affect the health of the child; however everything could change when this technique is used in humans. The scientific community will closely follow any child conceived using mitochondrial transfer to determine if it is safe to continue using.

The medical community is also concerned about the rapid expansion of this technology before these safety concerns have been addressed. This is especially true in places like the Ukraine, where this technology is not regulated; this is in contrast to the United States, where it is banned, or the United Kingdom, where it is conditionally allowed only to treat mitochondrial disorders. Dr. Valery Zukin, director of the Nadiya Clinic, leads a Ukrainian team that uses mitochondrial transfer to treat infertility. He has successfully helped at least 4 couples have seemingly healthy children using mitochondrial transfer, as these couples had failed to conceive through conventional in vitro fertilization (IVF). Before the birth of these children, it was unclear if the technique would work for general fertility issues, and it remains unknown what aspect of the treatment helps overcome these issues. Some speculate the donor mitochondria help overcome undiagnosed metabolic problems, but more research must be done before the medical community expands the technique.

Ethical Concerns

Ethicists are also concerned about the potential misuse of mitochondrial transfer. With the recent rise in genome editing technologies such as CRISPR-Cas9, bioethicists worldwide are calling for bans on alterations to genetic information passed on from parent to child. But this is exactly what happens when a daughter is born as a result of mitochondrial transfer; the daughter will carry mitochondrial DNA from a third unknown donor, which she will pass on to all of her future children. And if she has daughters, they will continue to pass on this donor DNA, affecting the genetic information of many generations to come in ways we cannot fully predict. This dilemma brings up an interesting question: should parents of mitochondrial transfer select only male embryos to prevent potentially changing the course of their blood line, or do parents have the right to have children of either sex despite the effect potential future generations?

As biology and safety concerns become better understood, the ethics and legal implications of this new technology will likely be debated and argued in courtrooms worldwide for years to come.

Catherine Weiner is a fifth-year Ph.D. candidate in the Department of Molecular and Cellular Biology and the Department of Genetics at Harvard University.

For more information:

To learn more about the inheritance patterns of mitochondrial disorders, see this article from the United Mitochondrial Disease Foundation

For more information on mitochondrial transfer techniques, see this article from Applied and Translational Genomics

To learn about the landmark sanction of mitochondrial transfer in the UK, see this excerpt from Nature